Esophageal carcinogenesis in the rat: zinc deficiency, DNA methylation and alkyltransferase activity.
Rats fed zinc-deficient diets and given an esophageal carcinogen, methylbenzylnitrosamine, develop tumors in greater incidence and with increased frequency compared to zinc-supplemented rats. This greater susceptibility is associated with a unique esophageal lesion, parakeratosis, with markedly increased epithelial necrosis and cell proliferation. Recent studies have shown that the increased susceptibility to tumorigenesis was further associated with a number of metabolic and biochemical alterations including increased binding of the carcinogen to DNA, shifts in O6-methylguanine (O6MeG)/7-methylguanine ratios and suggestions that the promutagen O6MeG lesion is not repaired effectively in the zinc-deficient esophagus; the latter was not reflected in the amount of O6-methyltransferase activity, however. The weight of evidence supports a presumption that zinc deficiency interferes with normal DNA repair mechanisms, the nature of which is not clear. An interesting additional finding was that zinc deficiency alone was associated with esophageal tumor induction, without carcinogen, which indicates that genetic material in the zinc-deficient esophageal epithelium is damaged sufficiently, without further chemical injury, to result in loss of control of cell proliferation. Manipulation of the time of exposure to zinc deficiency and carcinogen exposure defined the initiation period as most affected by the deficiency. Furthermore, reduced carcinogen exposure (and less toxicity), along with zinc deficiency, permits development of more tumors of the endophytic type, the form more relevant to human esophageal tumors. The groundwork, as described in this paper, has now been prepared to directly address the latter issue, endophytic tumors, and the putative relation of zinc deficiency to esophageal cancer in human populations.
Newberne
P M
PM
Mallory Institute of Pathology, Department of Pathology, Boston Medical Center, Mass., USA.
Broitman
S
S
Schrager
T F
TF
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism*; D004128:Dimethylnitrosamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000187:drug effects / Q000473:pathology; D008297:Male; D009336:Necrosis; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D010212:Papilloma / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000172:deficiency*
D002273:Carcinogens; D004273:DNA, Neoplasm; C014707:nitrosobenzylmethylamine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D015032:Zinc; D004128:Dimethylnitrosamine